Monoclonal Antibody Shows Promise in Ewing's Sarcoma

Action Points

Explain to interested patients that an experimental drug showed some therapeutic benefits for advanced Ewing's sarcoma in a small study, but that larger trials will be needed to confirm the findings.

A monoclonal antibody that targets an insulin-like growth-factor receptor was well tolerated and demonstrated antitumor activity in refractory Ewing's sarcoma, a phase I trial found.

Among 29 patients with advanced sarcomas treated with figitumumab, one patient had a complete objective response and one had a partial response, researchers reported online in Lancet Oncology.

An additional eight patients had disease stabilization lasting four months or longer, according to David Olmos, MD, of the Royal Marsden NHS Foundation Trust, in Sutton, England, and colleagues.

Severe adverse events included one case each of deep venous thrombosis, vomiting, and back pain, the researchers reported online in Lancet Oncology.

Current systemic treatment options for refractory sarcoma are few, and patients' prognosis is poor.

Twenty years of research has shown that the insulin-like growth factor (IGF) signaling pathway is involved in sarcomagenesis, and the IGF-1 receptor (IGF-1R) is a key regulator that seems to have a crucial role in tumor growth, metastasis, and angiogenesis.

Because case reports have also described antitumor effects in Ewing's sarcoma, Olmos and colleagues conducted two single-stage expansions of a phase I study of figitumumab in adults and children with various subtypes of sarcomas.

The first cohort included patients at least 18 years old with any subtype of sarcoma, and the second included patients 9 years or older with Ewing's sarcoma.

Between January 2006 and August 2008, 29 patients (21 male) were enrolled.

Median age was 30 years, six patients were 18 years or younger, and the specific subtype was Ewing's sarcoma in 16.

Figitumumab was given intravenously in doses of 20 mg/kg, once every three weeks in the first cohort and once every four weeks in the second, with treatment continuing until disease progressed or unacceptable toxicity developed.

All but one patient had received prior chemotherapy, 21 had had radiotherapy, and 20 had undergone surgery.

Safety assessments were done during each treatment cycle, and tumor response was assessed every six to eight weeks by CT, MRI, or both.

A total of 28 patients had at least one post-treatment scan and were considered evaluable.

The two patients who had confirmed responses both had Ewing's sarcoma, as did six patients who had disease stabilization ranging from four months to more than 16 months.

One patient with fibrosarcoma and another with synovial sarcoma also stabilized, while one patient with Ewing's sarcoma initially showed a partial response but subsequently developed a bone metastasis and was classified as having progressive disease.

"Nonprogression is widely considered to be an indicator of activity in sarcoma, and these results compare favorably with those of other targeted agents," the investigators wrote.

Safety concerns included clinically significant laboratory abnormalities, with a grade 4 elevation in uric acid in one patient, and grade 3-4 elevations in liver enzymes in another.

Four patients developed mild hyperglycemia and one developed moderate hyperglycemia that required treatment with oral antidiabetic medications.

"The mechanism for the observed hyperglycemia is unclear, although IGF-1R may be involved in glucose metabolism via crosstalk and heterodimerization with the insulin receptor," they explained.

Echocardiographic evaluations determined that there was no cardiac toxicity, with no substantial change in cardiac valve function or left ventricular ejection fraction.

This finding was noteworthy, according to the researchers, because IGF-1R is expressed on cardiac myocytes, and three-quarters of the patients had previously received potentially cardiotoxic anthracyclines.

Phase II studies of figitumumab are now completing accrual, and the development of predictive biomarkers of response "should be a priority," the investigators asserted.

Writing in an accompanying editorial, Jeffrey A. Toretsky, MD, of Georgetown University in Washington, D.C., and Richard Gorlick, MD, of the Albert Einstein College of Medicine in New York City, concurred.

"There is reason for optimism regarding the use of IGF-1R inhibitors in patients with Ewing's sarcoma; however, it is crucial to identify the subset of patients likely to respond," they wrote.

The relative lack of toxic effects -- particularly those seen with the traditional cytotoxic agents used for sarcomas -- suggests that this agent might be used in combination with standard chemotherapy.

"Ultimately, a phase III randomized study investigating the benefit of this combination might provide the proof of activity that will achieve the IGF-1R-pathway promise," Toretsky and Gorlick wrote.

The study was funded by Pfizer Global Research and Development.

Several of the investigators reported receiving funding from Pfizer Oncology, and three are employees of the company and own stock in the company.

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